Congenital intracardiac defects such as atrial septal defects, ventricular septal defects, and patent foramen ovale (PFO), a type of atrial septal defect, are well recognized intracardiac abnormalities in mammals. A PFO, for example, is a persistent, one-way, usually flap-like opening in the wall between the right atrium and left atrium of the heart. Since left atrial (LA) pressure is normally higher than right atrial (RA) pressure, the flap typically stays closed. Under certain conditions, however, RA pressure can exceed LA pressure, creating the possibility for right to left shunting of blood, permitting blood clots to enter the systemic circulation. In utero, the foramen ovale serves as a physiologic conduit for right-to-left shunting. After birth, with the establishment of pulmonary circulation, the increased left atrial blood flow and pressure results in functional closure of the foramen ovale. This functional closure is subsequently followed by anatomical closure of the two overlapping layers of tissue: the septum primum and septum secundum. However, autopsy studies have shown that a probe-detected patent foramen ovale (PFO) persists in up to approximately 25% of adults. Using contrast echocardiography (TEE), a patent foramen ovale can also be detected in approximately 25% of adults. These PFOs are congenital and are not typically the result of trauma, inflammation, ischemia or other underlying pathology associated with tissue injury. In effect, these defects are not the result of or surrounded by acutely injured tissue as would be found at the site of an acute myocardial infarct.
Studies have confirmed a strong association between the presence of a PFO and the risk for paradoxical embolism or stroke. Although the cause of ischemic stroke is not known, in approximately 40% of cases paradoxical embolism via a PFO is considered in the diagnosis, especially in young patients. In addition, there is evidence that patients with PFO and paradoxical embolism are at increased risk for future, recurrent cerebrovascular events.
Although the presence of a PFO has no therapeutic consequence in an otherwise healthy adult, patients suffering a stroke or transient ischemic attack (TIA) in the presence of a PFO and without another identifiable cause of the ischemic stroke are considered for prophylactic therapy to reduce the risk of a recurrent embolic event. These patients are commonly treated with oral anticoagulants, which have potential adverse side effects, such as hemorrhaging, hematoma, and interactions with a variety of other drugs. In certain cases, such as when anticoagulation is contraindicated, surgery may be used to close a PFO. Suturing a PFO closed typically requires attachment of the septum secundum to the septum primum with either continuous or interrupted sutures under direct visualization for example, by a thoracotomy, or via port access surgery.
Nonsurgical closure of PFOs and other congenital intracardiac defects have become possible with the advent of implantable umbrella closure devices and a variety of other similar mechanical closure designs, developed initially for percutaneous closure of atrial septal defects (ASD). These devices allow patients to avoid the potential side effects often associated with anticoagulation therapies. However, currently available designs of septal closure devices present drawbacks, such as high complication rates and residual leaks. In addition, since many septal closure devices were originally designed to close ASDs, which are true holes, rather than the flap-like anatomy of most PFOs, many closure devices lack the anatomic conformability to effectively close a PFO.
A need exists for a septal closure device or occluder that can provide complete closure of an intracardiac defect in a minimum amount of time, that has a lower complication rate, and that is simple and inexpensive to use and manufacture.
Alarmins are intracellular endogenous molecules that react to triggering events, including the presence of pathogens, misfolded or modified proteins, genomic alterations or exposed hydrophobic portions of molecules, by activating intracellular cascades that lead to a healing response. Alarmins, when released into the body's circulation, act as a signal of cell injury or disease. The body, in response to alarmins released from injured tissue, initiates a repair cascade that directs healing factors to the source of the signal, i.e., the injured tissue. The signal focuses and enhances the speed and intensity of the body's repair response to injury, resulting in accelerated healing. In particular, alarmins signal the mobilization and recruitment of progenitor or stem cells, for example, endothelial progenitor cells, to the site of the injured tissue.
Activation of alarmins requires that the alarmins' cysteines remain free (protonated) to maintain protein folding (and recognition by cognate receptors). Alarmins are inactivated when their cysteines are oxidized to form disulfide bonds. Further, the extracellular space of tissues undergoing highly inflammatory responses contains high amounts of free thiols, whereas those tissues undergoing less inflammatory responses contain smaller amounts of free thiols. Free thiols promote a reducing environment. Accordingly, in tissues that contain high amounts of free thiols, i.e., tissues which undergo highly inflammatory responses, alarmins are likely to be activated in the reducing environment.
The intracellular cytosol and the extracellular milieu are very different environments. The cytosol is highly reducing due to several thiol-regulating enzymatic systems, including the thioredoxin-thioredoxin reductase and glutaredoxin-GSH systems. The extracellular space is normally oxidized due to oxidizing agents including oxygen itself. In an intracellular environment, non-protein thiols, including GSH and cysteine, are most often found in a reduced state. Whereas, in an extracellular environment, non-protein thiols are most often found in the disulfide bond or oxidized form. The reduced or oxidized form of proteins thus depends on the compartments where they are found, e.g., extracellular or intracellular, and, when intracellular, cytosolic or within the endoplasmic reticulum. Cytoplasmic protein cysteine residues typically have free sulfhydryl groups, located in binding pockets of substrates, coenzymes, or metal cofactors, and take part directly in catalytic reactions. The cysteine residues are inactivated by oxidation and remain reduced in the presence of thiol-regulating systems.
Endogenous alarmins modulate the nature and magnitude of cellular injury to the host in addition to mobilizing host repair mechanisms. Alarmins are usually found in the cytosol and, when released into the extracellular space, trigger significant host responses. Host responses, for example, include activating endothelial cells and recruiting inflammatory cells, which promote wound healing and associated stromagenesis, angiogenesis, epithelial proliferation, and modulation of the immune response.
Alarmins trigger numerous wound healing events upon their release into the extracellular space. For example, the release of alarmins into the extracellular space leads to a dose-dependent increase in the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule, and RAGE and increased secretion of TNF-a, IL-8, monocyte chemotactic protein-1, plasminogen activator inhibitor 1, and tissue plasminogen activator. Through polygamous receptors, including RAGE, TLR2, and TLR4, alarmins signal upregulation of adhesion molecules in human endothelial cells, resulting in increased neutrophil recruitment. Extracellular alarmins also act as chemoattractants, leading to mesangioblast stem cell migration to injured tissues. Similarly, chronic alarmin delivery to normal muscle promotes endothelial cell permeability, proliferation, and angiogenesis. Primitive mesangioblasts and bone marrow-derived stem cells injected into mice preferentially migrate to sites of alarmin delivery. Alarmins from necrotic cells lead to increased angiogenesis through endothelial cell sprouting. In the setting of acute injury, alarmins play a role along with coordinate oxidative mechanisms to upregulate and drive TLR signaling. Together, these observations suggest that the earliest events in response to necrotic death drive developments of pro-oxidant mechanisms designed to clear debris and drive the wound-healing process.
An alarmin activator is any substance capable of inducing or maintaining activity of an alarmin. For example, certain alarmins are active when their cysteine residues are free, to maintain protein folding and recognition by cognate receptors, rather than oxidized to form intramolecular or intermolecular disulfide bonds. Accordingly, certain reducing agents act as alarmin activators by protonating or maintaining protonation of cysteine residues in extracellular alarmin molecules present in the tissue microenvironment.
A need exists for a method of adhering or bonding an alarmin or an alarmin activator to a septal closure device or occluder that can provide complete closure of an intracardiac defect, and that is simple and inexpensive to manufacture.